CONFORMATIONAL-ANALYSIS BY NMR-SPECTROSCOPY, MOLECULAR-DYNAMICS SIMULATION IN WATER AND X-RAY CRYSTALLOGRAPHY OF GLUTAMIC-ACID ANALOGS - ISOMERS OF 1-AMINOCYCLOPENTANE-1,3-DICARBOXYLIC ACID

The conformational analysis of two isomeric glutamic acid analogues co ntaining a cyclopentane ring, substituted in position 1 by an amino an d a carboxyl group, and-in position 3 by a second-carboxyl group has b een carried out in an aqueous environment, by H-1 and C-13 NMR spectro scopy, and molecular dynamics (MD). The X-ray structure of the trans-i somer is included in this study. These cis and trans analogues may dis play envelope E or 'twist' T conformations in aqueous solution. The de finition of cis and a ans is relative to the arrangement of the carbox yl function. This study shows four conformational families I-rv with c haracteristic distances between the potentially active functional grou ps, alpha-NH-(+)(3)-gamma-CO2- and alpha-CO2--gamma-CO2-. At physiolog ical pi, the amino group in the cis-isomer 1 is found to be axial ((2) E or E(3) conformers), both carboxyl groups being in equatorial positi ons to reduce the steric energy (type II). In the trans-isomer 2, a 1, 3-electrostatic attraction stabilizes the E(1) or (5)E conformers with the alpha-NH3+ and gamma-CO2- in an axial or isoclinal position, (typ e I). Conversely, at isoelectric pH when the 3-carboxylate group is pr otonated, each isomer is represented by new privileged conformations. The cis-isomer 1 exhibits a E(5) conformation in which the l-carboxyla te group, alpha-CO2-, is axial and stabilized by an electrostatic inte raction with the 3-carboxyl group, gamma-CO2H, less equatorial (type I V). For the trans-isomer 2, the steric parameters favour the E(2) or ( 3)E conformations, in which the two carboxy groups are shown to be equ atorial or isoclinal and the amino group axial (type III). The data ob tained may be considered as important elements in the recognition feat ures of these glutamic acid analogues in biological systems (NMDA or A CPD receptors of the central nervous system, glutamine synthetase, D-g lutamate-adding enzyme, etc.).